Publications

Recent advances in single-cell RNA sequencing and lineage tracing techniques have provided valuable insights into the temporal changes in gene expression during development, tumor progression, and disease onset. However, there are few computational methods available to analyze this information to help understand multicellular dynamics. We introduce Deep Lineage, a deep-learning method for analyzing time-series single-cell RNA sequencing with matched lineage tracing data. Our method accurately...

CONCLUSIONS AND RELEVANCE: This GBD 2023 analysis found that anorexia nervosa and bulimia nervosa contribute substantially to global nonfatal health loss. These findings support the integration of eating disorders into mental health surveillance, prevention, and service planning worldwide.

ClpP protease maintains proteostasis in human mitochondria and is overexpressed in cancers such as acute myeloid leukemia (AML). While activators such as dordaviprone (ONC201) have reached the clinic, the development of ClpP inhibitors has been hampered by paradoxical activation upon orthosteric inhibitor binding. Here, we report a series of quinazolinone-based compounds that allosterically inhibit human ClpP with nanomolar potency. Cryo-EM and H/D exchange mass spectrometry reveal that our lead...

Sialic acid (Neu5Ac) is a monosaccharide terminating glycoconjugates, serving as ligands for lectins in health and disease. Tools to target sialyltransferases (STs) and neuraminidases (NEUs) are important in the study of sialoglycans. 3FaxNeu5Ac is a common ST inhibitor, while 2,3diFNeu5Ac is a covalent mechanism-based NEU inactivator. Here, we demonstrate the advantages of having two fluorines at C3 for both classes of inhibitors. Motivated by the finding that 3FaxNeu5Ac is transferred by STs...

Effector-triggered immunity (ETI), mediated by nucleotide-binding leucine-rich repeat immune receptors (NLRs), plays a critical role in protecting plants from pathogens. While the scope of ETI elicited by Pseudomonas syringae type III effectors on Arabidopsis thaliana has been characterized, no equivalent study has been performed on related oilseed crops, limiting our ability to translate fundamental plant immunity research into crop protection strategies. Here, we present a comprehensive screen...

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CONCLUSION: BRIDGES-NBS has established a condition list for implementation across multiple state and territorial PHLPs, enabling the prospective evaluation of feasibility of population-wide genomic NBS.

In lytic infection, Epstein-Barr virus (EBV) proteins manipulate cellular processes in multiple ways to facilitate virion production and overcome host antiviral responses. Here, we screened a library of EBV lytic proteins for those that manipulate or localize to cellular processing bodies (PBs), known to play important roles in RNA surveillance and miRNA-mediated translational control. One EBV protein, BRRF1, was identified that partially localized to PBs, and affinity purification-mass...

The ClpXP ATP-dependent unfoldase-protease complex plays important roles in maintaining protein homeostasis in the mitochondria. Pathogenic variants of CLPP have been identified in patients with Perrault syndrome type 3 (PRLTS3), a rare recessive mitochondrial disease characterized by sensorineural hearing loss, ovarian dysfunction, and neurological abnormalities. However, it remains unclear how these ClpP variants cause this disease. Here we identify three cellular substrates of ClpXP using...

Development of long-read RNA sequencing technologies has paved the way to the exploration of RNA isoform diversity and its relevance in regulating cell fate. However, identifying new functional isoforms is still very difficult. Here, we leverage long-read RNA sequencing to study changes in isoforms during somatic cell reprogramming and identify novel isoforms occurring throughout cell state transitions. We demonstrate tight regulation of non-coding isoforms and show that isoform switching plays...

High-content cell imaging approaches enable the systematic characterization of cellular function through the acquisition of multimodal information from large cohorts of live single cells. Yet, due to their scale and complexity, data acquired via such approaches are often challenging to meaningfully share across laboratories and effectively use for independent studies. Since its inception, the main purpose of TheCellVision.org repository has been to fill this gap, providing the research community...

Despite long-standing knowledge of the significant contribution of lifestyle factors in the development of chronic conditions, lifestyle preventive strategies have failed to lower chronic disease rates globally [1,2]. Personal digital health technologies (P-DHTs) that can be worn on the person (wearables, smart devices and mobile phones) can be used for self-monitoring directly by the individual increasing health agency and access, with promise for transformation in health prevention. While...

CONCLUSIONS: Mail-based self-collected DBS enables remote testing by allowing nonmedically trained individuals to reliably collect their own samples. High concordance and acceptability indicate that this method is viable for addressing health care access challenges, particularly in populations motivated to seek testing.

Combination therapy with broadly neutralizing antibodies (bNAbs) holds great promise for human immunodeficiency virus (HIV) functional cure, yet a critical question remains: when multiple bNAbs with distinct pharmacokinetic and pharmacodynamic properties are available, which combinations are most effective, and what determines their performance? To address this, we develop an impulsive differential equation model that incorporates three bNAb mechanisms, namely blocking viral entry, enhancing...

The first draft diploid genome assembly (HuRef) of an individual in 2007 was a milestone in genomics. Here, we report HuRef2.0, a revision of HuRef assembled using only Oxford Nanopore Technologies (ONT) Simplex-reads and the hifiasm assembler. Results are close in continuity to the telomere-to-telomere (T2T) assemblies but were assembled from standard DNA samples without using multiple sequencing and mapping technologies, including ultra-long-reads and/or proximity-ligation. Three ONT flowcells...

CONCLUSION: Two agnostic, data-driven models identified several occupations associated with both increased and decreased lung cancer risks. These associations persisted after accounting for known exposures and covariates, highlighting the need to investigate unidentified occupational factors.

CONCLUSIONS: Treatment with semaglutide modulated explore/exploit behaviors in patients with MDD. These results highlight the role of metabolic mechanisms in decision-making processes in MDD and expand knowledge of the potential neuropsychiatric effects of GLP-1RAs.

Microbial constituents in the gastrointestinal tract, the urine and prostate tissue are being linked with clinical differences in prostate cancer, and a recent meta-analysis has linked periodontal disease to this cancer. Several hypotheses exist regarding how specific bacteria can contribute towards the development of prostate cancer. Recovering microbial genomes, and their genomic features, from clinical samples and investigating fine-scale taxonomy is a critical first step in investigating...

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Cys2-His2-zinc-finger proteins (C2H2-ZFPs) form the largest class of human transcription factors, yet their potential roles in higher-order genome organization remain poorly defined. To date, only a few C2H2-ZFPs, e.g. CTCF, have been implicated in chromatin organization. Here, we systematically examined the global relationship between C2H2-ZFPs and long-range chromatin interactions (LRIs). By integrating ChIP-seq datasets for 216 C2H2-ZFPs with genome-wide chromatin interaction maps, we find...